It is generally known to provide a substrate, such as a medical device or parts of such a device with various types of coatings for enhancing the biocompatability of the device when it is introduced into a mammal, such as a human body.
In particular, implantable medical devices used for minimally invasive procedures in body conduits, such as for example in blood vessels, the esophagus or urethra may be provided with bio-compatible coatings. Among the various intraluminal prostheses commonly used today are vascular grafts which include endovascular grafts, stents and graft-stent combinations. Various types of stents are available such as wire stents and tubular stents. These constructions may be made from metals or polymers and may be of the balloon expandable type or the self-expanding type. Among the self-expanding type are those made from superelastic, shape-memory materials such as nitinol. Other devices which can benefit from such coatings include catheters, guide wires, trocars, introducer sheaths and the like.
Medical devices coated with bio-compatible coatings and methods for providing substrates with such coatings have been described in a number of references, some of which are described below.
Various biocompatible coatings have been employed with medical devices in an attempt to impart enhanced bio-compatibility and other properties to such devices. For example, therapeutic agents have been incorporated into polymeric films made from polyurethane, polyester, polylactic acid, polyamino acid, polyorthoester, polyphosphate ester and the like, as disclosed in U.S. Pat. No. 5,282,823, U.S. Pat. No. 5,163,958 discloses a stent having a binder layer and an anti-thrombogenic pyrolytic amorphous carbon layer attached to the binder layer to provide an anti-thrombogenic surface.
Biologically active agents have been incorporated into polymeric films for slow or controlled release of the active agent into the body. For example, U.S. Pat. No. 5,342,348 discloses porous polyurethane and PTFE stents having biodegradable polymeric filaments attached thereto which release drug over time. U.S. Pat. No. 5,383,928 discloses delivery of a drug using a stent-sheath structure made from both degradable and non-degradable polymers, such as ethylene vinyl acetate (EVA).
Endoprostheses have also been developed for targeted drug delivery to sites within a body. Such endoprostheses can be coated with microporous materials having pores in which bio-active agents may be anchored for controlled delivery thereof over time. In particular, U.S. Pat. No. 5,449,382 to Dayton (hereinafter the "'382 patent") discloses a minimally invasive bio-activated endoprosthesis for vessel repair. This endoprosthesis is coated with a polymer having a microporous structure with a predetermined pore size and a bio-active substance disposed within these pores for elution therefrom. The coating described by the '382 patent is made from a polymeric solution which includes silicone, polyurethane, polyvinyl alcohol, polyethylene, biodegradable polylactic acid polymers, polyglycolic acid polymers, polyesters, hydrogels, tetrafluoroethylene, polytetrafluoroethylene, fluorosilicone etc. Admixed into one of these polymers is a bio-active agent, such as for example heparin, for controlled and prolonged release thereof.
One drawback to conventional biocompatible coatings is the use of organic solvents. Such organic solvents may be highly reactive in vivo if not completely removed prior to implantation. Furthermore, in instances where the bio-active agent is admixed with the polymer, the surface of the article coated with such a composition is not necessarily continuously bio-active, i.e., active throughout the entire surface. Thus, such a coating may be less effective at preventing, e.g., thrombosis formation, than coatings which are designed to provide resistance to thrombosis throughout the surface.
Although polyurethane coatings have been employed as biomaterials, they are known to suffer from stability problems and such coatings are quickly bio-degraded and or bio-eroded. Thus, attempts have been made to develop medical devices and polyurethane coatings therefor which contain compositions which are less susceptible to bio-degradation and bio-erosion.
In particular, U.S. Pat. No. 5,133,742 to Pinchuk (hereinafter the "'742 patent") discloses a prosthesis formed from polycarbonate-urethane polymers. Such polycarbonate-urethane compositions are bio-compatible and less susceptible to bio-degradation and/or bio-erosion than simple polyurethane coatings. The '742 patent describes forming the polycarbonate-urethane polymer from the reaction of a polycarbonate diol, a diisocyanate and a chain extender in a suitable organic solvent. This polymer is then spun through a spinnerette into a filamentous vascular graft. Prostheses formed entirely from such a composition, however, are expensive to produce.
U.S. Pat. No. 5,575,818 to Pinchuk discloses a locking ring or barb-type braided stent coated or lined with porous bio-compatible coating materials which include polyurethane, spun polyurethane, spun polycarbonate urethane, spun polyolefin, silicone coated polyurethane, spun silicone and combinations thereof. This patent, however, suffers from the drawback, that most of the materials, including the spun polycarbonate urethane coatings or linings are applied in a non-efficient, labor intensive manner. In particular, the preferred method for forming the liner or coating includes spinning the polymer on a mandrel at an angle coincident with the pitch angle of the stent (i.e., the pitch angle of the stent's body section, as well as, the locking ring ends thereof). The lining is then applied to an adhesive-covered stent.
EP Publication No. 627 226 to Severini (hereinafter the "Severini publication") also describes a stent which is coated with a polycarbonate-urethane composition. This coating composition, however, suffers from the drawback that it is applied to the stent as a segmented thermoplastic polycarbonate-urethane solution containing an organic solvent, such as dimethylacetamide. A stent coated with such a composition is clearly not desirable because of the danger to the patient should all of the organic solvent not be evaporated prior to implantation. Furthermore, the evaporation of organic solvents, such as dimethylacetamide, not only increases the health risks to manufacturing personnel but also pollutes the environment. Moreover, the required evaporation step adds a significant amount of time to the coating process, i.e., 24 hours. Still further, in the Severini publication, the process of applying the polycarbonate-urethane coating to the stent is slow and inefficient. In particular, the process includes rotating the stent at a speed of 2 rpm while the coating is dripped onto the stent from a pipette suspended thereover. Coatings formed in such a manner are unequal and nonuniform.
The present invention is directed to aqueous dispersions or emulsions of polycarbonate-polyurethane coatings for implantable devices and methods of preparation thereof. These coatings are particularly advantageous because they make it possible to impart implantable devices with long-term biostability and such coatings serve as superior primer layers for attachment of optional bio-active agents. Furthermore, due to the aqueous-based nature of the coatings of the present invention, they are less hazardous than the prior art coatings cited hereinabove. Moreover, these coatings are highly versatile and can be efficiently applied to a wide range of substrates including heat sensitive. substrates, such as, polyethyleneterphlate (PET) balloon catheters and stents. Because the optional bio-active agents of the present invention are covalently bonded to the polycarbonate-polyurethane primer, the bio-active agents are permanently attached to the substrate unlike certain of the transient coatings discussed above.
In summary, all of the references cited above suffer from the drawback that they use organic solvents in their coating layer and/or cure at high temperatures. Thus, there is a need for improved bio-compatible coatings which enhance the biostability, abrasion-resistance, lubricity and bio-activity of the surface of implantable medical devices, especially heat sensitive medical devices and coatings which have heat-sensitive biomolecules. In particular, there is a need for improved, cost efficient compositions and devices which have antithrombogenic properties and for more efficient methods of providing same. The present invention is directed to meeting these and other needs.